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Grand Rounds Conference Jinghua Chen, MD, PhD University of Louisville Department of Ophthalmology and Visual Sciences April 3, 2015
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History CC: Progressive decreased central vision OU for one year. HPI: 27 year old white male presented with progressive decrease central vision with spots in front of both eyes for one year. Patient has known macular changes since 2006.
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Past Medical History POH: Moderate myopia (-3.50 D OU) Known “macular issue” since 2006 PMH: None Allergy: NKDA FH: Mother “night vision issue” Medication: None
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Exam ODOS ODOS BCVA: 20/2020/20 Pupils: 4 2 4 2 No RAPD OU IOP: 1211 EOM/CVF:Full OU Ant. Seg: Normal OU Color vision: 9/12 11/12
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IR Photos Grainy perifoveal RPE stippling (hyperplasia/atrophy)
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OCT Retina Central macular atrophy, RPE foveal thinning with overlying loss of photoreceptors, OD>OS
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FA FA: Bull’s eye maculopathy with perifoveal patchy ring window defect OU, no leakage
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Late Phase FA Central hypofluorescence with perifoveal hyperfluorescence fading of window defect
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Assessment and Plan 27 year old male with known macular changes since 2006 with more eccentric fixation in last year with Bull’s eye maculopathy OU. 27 year old male with known macular changes since 2006 with more eccentric fixation in last year with Bull’s eye maculopathy OU. Differential Diagnosis Differential Diagnosis Cone dystrophy Cone dystrophy Stargardt’s disease Stargardt’s disease Cone-rod dystrophy Cone-rod dystrophy Central areolar choroidal atrophy Central areolar choroidal atrophy Chronic macular hole Chronic macular hole Fenestrated sheen macular dystrophy Fenestrated sheen macular dystrophy Benign concentric annular macular dystrophy Benign concentric annular macular dystrophy Olivopontocerebellar atrophy (OPCA) Olivopontocerebellar atrophy (OPCA) Ceroid lipofuscinosis Ceroid lipofuscinosis Plan: mf ERG, HVF 10-2 Plan: mf ERG, HVF 10-2 BSCS 2014-2015 Book 12, Retina and Vitreous: 236
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mf ERG mf ERG Extinguished foveal and decreased parafoveal and peripheral responses OU Delayed P1 implicit time involving fovea OU and parafovea and periphery OD
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mf ERG First Order Traces Cone photoreceptor dysfunction
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HVF 10-2 OU: central scotoma OD > OS
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Diagnosis and Management Diagnosis: Progressive cone dystrophy Diagnosis: Progressive cone dystrophy Management: Management: Observation Observation Sunglasses for photophobia Sunglasses for photophobia Macular Dystrophy Support Group (per patient’s request) Macular Dystrophy Support Group (per patient’s request)
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Photoreceptor Degeneration Cone dystrophy (photophobia, abnormal color vision and diminished central vision) Cone dystrophy (photophobia, abnormal color vision and diminished central vision) Cone-rod dystrophy (early decrease in central visual acuity, photophobia, color vision defects, and nystagmus, with later development of night blindness (nyctalopia). Cone-rod dystrophy (early decrease in central visual acuity, photophobia, color vision defects, and nystagmus, with later development of night blindness (nyctalopia). Rod-cone dystrophy (nyctalopia and progressive peripheral vision loss.) Rod-cone dystrophy (nyctalopia and progressive peripheral vision loss.)
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Progressive Cone Dystrophy The prevalence of cone-rod dystrophy is approximately 1/40,000 The prevalence of cone-rod dystrophy is approximately 1/40,000 Heterogeneous group of diseases Heterogeneous group of diseases Onset in teenage or later adult years Onset in teenage or later adult years Secondary rod photoreceptor involvement Secondary rod photoreceptor involvement Overlap between progressive cone and cone-rod dystrophy Overlap between progressive cone and cone-rod dystrophy Abnormal photopic ERG, normal rod-isolated ERG Abnormal photopic ERG, normal rod-isolated ERG Hamel CP. Orphanet J Rare Dis. 2007; 2:7. Thiadens AA, Ophthalmology. 2012; 119:819–26
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Genetics Dominant cone dystrophy Dominant cone dystrophy 6p21.1 is caused by mutations in the GUCA1A gene, which codes for guanylate cyclase activator, a calcium-binding protein in photoreceptor outer segments 6p21.1 is caused by mutations in the GUCA1A gene, which codes for guanylate cyclase activator, a calcium-binding protein in photoreceptor outer segments Mutation in GUCY2D at 17p13.1 Mutation in GUCY2D at 17p13.1 Autosomal recessive cone dystrophy Autosomal recessive cone dystrophy ABCA4 (1p21-p23) gene, which encodes an ATP-binding cassette (ABC) transporter protein expressed by rod and cone disc membrane and is involved in the transport of vitamin A derivatives to RPE. (ABCA4 also have been implicated in Stargardt’s disease, cone-rod dystrophy, and ‘‘retinitis pigmentosa.’’) ABCA4 (1p21-p23) gene, which encodes an ATP-binding cassette (ABC) transporter protein expressed by rod and cone disc membrane and is involved in the transport of vitamin A derivatives to RPE. (ABCA4 also have been implicated in Stargardt’s disease, cone-rod dystrophy, and ‘‘retinitis pigmentosa.’’) X-linked recessive: Tapetal-like sheen, Mizuo-Nakamura phenomenon X-linked recessive: Tapetal-like sheen, Mizuo-Nakamura phenomenon
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Management Cone photoreceptor transplantation: Adult Nrl ‐ / ‐ mice expressed only cone-specific genes (PNA, s ‐ opsin and cone arrestin) in photoreceptors, and did not express rod ‐ specific genes (Nrl or rhodopsin) Purified these cone photoreceptors from the mouse retina based on the CD73 cell surface antigen. Transplantation of postnatal day 4 cells into wild type mouse retina mediated optimal integration into the outer nuclear layer (ONL) generating morphologically mature photoreceptors. Restoring daylight vision to AMD, cone ‐ rod dystrophies, or late-stage RP Gene therapy RPGRIP1-deficient dog: a large animal model of cone-rod dystrophy. (Mol Ther. 2014 Feb)Mol Ther. Non allele-specific RNAi knockdown of GCAP1 as a general therapeutic strategy to rescue any GCAP1-based dominant cone-rod dystrophy in human patients. (PLoS One. 2013)PLoS One. Suppressing thyroid hormone Signaling Suppressing thyroid hormone Signaling Preserves cone photoreceptors in mouse models of retinal degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina.(Proc Natl Acad Sci U S A. 2014 Mar)Proc Natl Acad Sci U S A. Low vision aids Low vision aids http://www.stemcellsportal.com/first-step-towards-treating-cone-photoreceptor-degeneration
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References BSCS 2014-2015 Book 12, Retina and Vitreous: 232-236 BSCS 2014-2015 Book 12, Retina and Vitreous: 232-236 Berger W, Kloeckener-Gruissem B, and Neidhardt J The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 2010;29:335-375 Gardner JC, Liew G, Quan YH. Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.,. doi: 10.1002/humu.22679. Gardner JC, Liew G, Quan YH. Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.,Hum Mutat. 2014 Nov;35(11):1354-62. doi: 10.1002/humu.22679. Gardner JCLiew GQuan YH Gardner JCLiew GQuan YHHum Mutat. Durlu YK, Köroğlu Ç, Tolun A. Novel recessive cone-rod dystrophy caused by POC1B mutation. JAMA Ophthalmol. 2014 Oct;132(10):1185-91. Durlu YK, Köroğlu Ç, Tolun A. Novel recessive cone-rod dystrophy caused by POC1B mutation. JAMA Ophthalmol. 2014 Oct;132(10):1185-91. Durlu YKKöroğlu ÇTolun AJAMA Ophthalmol. Durlu YKKöroğlu ÇTolun AJAMA Ophthalmol. Rabin J. Quantification of color vision with cone contrast sensitivity. Vis Neurosci. 2004 May-Jun;21(3):483- 5. Rabin J. Quantification of color vision with cone contrast sensitivity. Vis Neurosci. 2004 May-Jun;21(3):483- 5.Quantification of color vision with cone contrast sensitivity.Quantification of color vision with cone contrast sensitivity. Kearns TP, Hollenhorst RW. Chloroquine retinopathy: evaluation by fluorescein fundus angiography. Arch Ophthalmol. 1966;76: 378–384. Kearns TP, Hollenhorst RW. Chloroquine retinopathy: evaluation by fluorescein fundus angiography. Arch Ophthalmol. 1966;76: 378–384. Deutman AF. Benign concentric annular macular dystrophy. Am J Ophthalmol. 1974;78:384–396. Deutman AF. Benign concentric annular macular dystrophy. Am J Ophthalmol. 1974;78:384–396. Fishman GA, Fishman M, Maggiano J. Macular lesions associated with retinitis pigmentosa. Arch Ophthalmol. 1977;95:798–803. Fishman GA, Fishman M, Maggiano J. Macular lesions associated with retinitis pigmentosa. Arch Ophthalmol. 1977;95:798–803. Michaelides M, Hardcastle AJ, Hunt DM, Moore AT. Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. Surv Ophthalmol. 2006;51:232–258. Michaelides M, Hardcastle AJ, Hunt DM, Moore AT. Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. Surv Ophthalmol. 2006;51:232–258. O’Donnell FE Jr, Welch RB. Fenestrated sheen macular dystrophy: a new autosomal dominant maculopathy. Arch Ophthalmol. 1979; 97:1292–1296. O’Donnell FE Jr, Welch RB. Fenestrated sheen macular dystrophy: a new autosomal dominant maculopathy. Arch Ophthalmol. 1979; 97:1292–1296. Kurz-Levin MM, Halfyard AS, Bunce C, et al. Clinical variations in assessment of bull’s-eye maculopathy. Arch Ophthalmol. 2002; 120:567–575. Kurz-Levin MM, Halfyard AS, Bunce C, et al. Clinical variations in assessment of bull’s-eye maculopathy. Arch Ophthalmol. 2002; 120:567–575.
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References Hartong, D.T., Berson, E.L., and Dryja, T.P. (2006). Retinitis pigmentosa. Lancet 368, 1795–1809. Hartong, D.T., Berson, E.L., and Dryja, T.P. (2006). Retinitis pigmentosa. Lancet 368, 1795–1809. El Shamieh S, Neuillé M, Terray A, Orhan E, Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy. The American Journal of Human Genetics 94, 625–633 El Shamieh S, Neuillé M, Terray A, Orhan E, Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy. The American Journal of Human Genetics 94, 625–633 El Shamieh SNeuillé MTerray AOrhan E El Shamieh SNeuillé MTerray AOrhan E Nogueira HM 1, Gama RD. Images in clinical medicine. Bull's-eye maculopathy. N Engl J Med. 2009 May 21;360(21):2224. doi: 10.1056/NEJMicm0708021. Nogueira HM 1, Gama RD. Images in clinical medicine. Bull's-eye maculopathy. N Engl J Med. 2009 May 21;360(21):2224. doi: 10.1056/NEJMicm0708021. Nogueira HMGama RDN Engl J Med. Nogueira HMGama RDN Engl J Med. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7. Thiadens AA, Phan TM, Lotery AJ. Clinical Course, Genetic Etiology, and Visual Outcome in Cone and Cone- Rod Dystrophy. Ophthalmology. 2012;119:819–26. Thiadens AA, Phan TM, Lotery AJ. Clinical Course, Genetic Etiology, and Visual Outcome in Cone and Cone- Rod Dystrophy. Ophthalmology. 2012;119:819–26. Lhériteau E, Petit L, Weber M. Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. Mol Ther. 2014 Feb;22(2):265-77. doi: 10.1038/mt.2013.232. Epub 2013 Oct 4. Lhériteau E, Petit L, Weber M. Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. Mol Ther. 2014 Feb;22(2):265-77. doi: 10.1038/mt.2013.232. Epub 2013 Oct 4. Lhériteau EPetit LWeber M Mol Ther. Lhériteau EPetit LWeber M Mol Ther. Jiang L, Li TZ, Boye SE. RNAi-mediated gene suppression in a GCAP1(L151F) cone-rod dystrophy mouse model. PLoS One. 2013;8(3):e57676. doi: 10.1371/journal.pone.0057676. Epub 2013 Mar 5. Jiang L, Li TZ, Boye SE. RNAi-mediated gene suppression in a GCAP1(L151F) cone-rod dystrophy mouse model. PLoS One. 2013;8(3):e57676. doi: 10.1371/journal.pone.0057676. Epub 2013 Mar 5. Jiang LLi TZBoye SEPLoS One. Jiang LLi TZBoye SEPLoS One. Ma H, Thapa A, Morris L. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3602-7. doi: 10.1073/pnas.1317041111. Epub 2014 Feb 18. Ma H, Thapa A, Morris L. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3602-7. doi: 10.1073/pnas.1317041111. Epub 2014 Feb 18. Ma HThapa AMorris LProc Natl Acad Sci U S A. Ma HThapa AMorris LProc Natl Acad Sci U S A.
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